Circulation-active substituted 1,4-dihydropyridine-3-carboxylic acid piperazides

ABSTRACT

1,4-Dihydropyridine-3-carboxylic acid piperazides of the formula ##STR1## in which R 1  is CN or alkyl, preferably methyl, 
     R 2  is H, CN, NO 2  or preferably carboxyalkyl, 
     R 3  is aryl or heterocyclic, and 
     R 4  is alkyl, cycloalkyl, aryl or an acyl radical, 
     and physiologically acceptable salts thereof, are circulation active. Novel intermediates are also provided.

The invention relates to 1.4-dihydropyridine-3-carboxylic acidpiperazides, to process for their preparation and to their use inmedicaments.

It is known that 1.4-dihydropyridines have vasodilating properties andcan be used as antihypertensives (compare DE-OS (German PublishedSpecification) No. 2,629,892 and DE-OS (German Published Specification)No. 2,752,820).

It is also known that dihydropyridinecarboxamides effect limitation ofthe contractility of the smooth and cardiac muscles and can be used forthe treatment of coronary and vascular diseases (compare DE-OS (GermanPublished Specification) No. 2,228,377).

The invention relates to 1,4-dihydropyridine-3-carboxylic acidpiperazides of the general formula I ##STR2## in which R¹ representscyano or represents straight-chain or branched C₁ -C₆ -alkyl which isoptionally substituted by halogen, hydroxyl or C₂ -C₇ -acyloxy,

R² represents hydrogen, represents cyano, represents nitro or representsthe group CO₂ R⁵, R⁵ denoting straight-chain or branched C₁ -C₈ -alkylwhich is optionally substituted by hydroxyl, halogen, cyano, C₁ -C₈-alkoxy, C₁ -C₈ -alkylthio, phenyl, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alkylamino, phenylamino, C₂ -C₇ -acylamino or C₁ -C₆-alkyl-benzyl-amino,

R³ represents C₆ -C₁₂ -aryl which is optionally substituted once orseveral times, identically or differently, by halogen, nitro, cyano, C₁-C₈ -alkyl, C₁ -C₈ -alkoxy, C₁ -C₈ -alkylthio, C₇ -C₁₄ -aralkyl, C₇ -C₁₄-aralkoxy or C₇ -C₁₄ -aralkylthio, it being possible for each of thearyl radicals in turn to be substituted by nitro, trifluoromethyl,cyano, methoxy, methylthio, trifluoromethoxy, difluoromethoxy, halogenor C₁ -C₆ -alkyl, or is optionally substituted by trifluoromethyl,trifluoromethylthio, trifluoromethoxy, difluoromethoxy, amino, C₁ -C₆-alkylamino, di-C₁ -C₆ -alkylamino or by C₂ -C₇ -acylamino, orrepresents a heterocycle from the series comprising pyridyl, thienyl,furyl, pyrrolyl, quinolyl, isoquinolyl, pyrimidyl, benzoxadiazolyl,imidazolyl, thiazolyl, oxazolyl, chromenyl, or thiochromenyl, theheterocycle optionally being substituted by phenyl, C₁ -C₆ -alkyl, C₁-C₆ -alkoxy, C₁ -C₆ -alkylthio, trifluoromethyl, tri-fluoromethoxy,trifluoromethylthio, halogen, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alkylamino or C₂ -C₇ -acylamino, and

R⁴ represents C₆ -C₁₂ -aryl which is optionally substituted once orseveral times, identically or differently, by halogen, nitro, cyano, C₁-C₈ -alkyl, C₁ -C₈ -alkoxy, C₁ -C₈ -alkylthio, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, difluoromethoxy, hydroxyl, amino,C₁ -C₆ -alkylamino, di-C₁ -C₆ -alkylamino or C₂ -C₇ -acylamino, orrepresents straight-chain, branched or cyclic C₁ -C₂₀ -alkyl, C₂ -C₂₀-alkenyl or C₂ -C₂₀ -alkynyl, each of which can optionally besubstituted by halogen, C₁ -C₈ -alkoxy, C₁ -C₈ -alkylthio, amino, C₁ -C₈-alkylamino, di-C₁ -C₈ -alkylamino, C₂ -C₇ -acylamino, piperidino,piperazino, morpholino, thiomorpholino, pyrrolidino or by C₆ -C₁₂ -aryl,it being possible for aryl in turn to carry one or more substituentsfrom the group comprising nitro, cyano, trifluoromethyl, halogen, C₁ -C₈-alkyl, C₁ -C₈ -alkylthio or C₁ -C₈ -alkoxy, or is substituted by thegroup COR⁶,

R⁶ representing hydrogen, representing hydroxyl, representing C₁ -C₈-alkoxy or representing the group ##STR3## R⁷ and R⁸ being identical ordifferent and denoting hydrogen, C₁ -C₈ -alkyl, C₆ --C₁₂ -aryl, C₇ -C₁₄-aralkyl or C₂ -C₇ -acyl, or

R⁷ and R⁸ together forming a 5-7-membered saturated or unsaturated ringwhich can contain as further hetero atoms nitrogen, sulphur and/oroxygen, or

R⁴ represents the group COR⁶,

R⁶ having the abovementioned meaning,

in the form of their isomers, isomer mixtures, racemates and opticalantipodes, and to their physiologically acceptable salts.

Preferred compounds of the general formula I are those

in which

R¹ represents straight-chain or branched C₁ -C₄ -alkyl, which isoptionally substituted by one or more fluorine, chlorine, bromine,hydroxyl, benzoyloxy or acetyloxy,

R² represents cyano, represents nitro, or represents the group CO₂ R⁵,

R⁵ denoting straight-chain or branched C₁ -C₆ -alkyl which is optionallysubstituted by one or more fluorine, chlorine, bromine, cyano, phenyl,C₁ -C₆ -alkoxy, C₁ -C₆ -alkylthio, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄-alkylamino, acetylamino or benzylmethylamino,

R³ represents phenyl which is optionally substituted up to four times,identically or differently, by fluorine, chlorine, bromine, nitro,cyano, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, C₁ -C₆ -alkylthio, benzyl,benzyloxy or benzylthio, it being possible for each of the phenylradicals in turn to be substituted by nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, methoxy, fluorine, chlorine,bromine or C₁ -C₄ -alkyl, or is substituted by trifluoromethyl,trifluoromethoxy, difluoromethoxy, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄-alkylamino or acetylamino or acetylamino, or represents pyridyl,thienyl, furyl, pyrimidyl, benzoxadiazolyl, 2-phenyl-thiochromen-8-yl orquinolyl, and

R⁴ represents phenyl which is optionally substituted up to four times,identically or differently, by fluorine, chlorine, bromine, nitro,cyano, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, C₁ -C₆ -alkylthio,trifluoromethyl, difluoromethoxy, hydroxyl, amino, C₁ -C₃ -alkylamino,di-C₁ -C₃ -alkylamino or acetylamino, or represents straight-chain,branched or cyclic C₁ -C₁₅ -alkyl, C₂ -C₁₅ -alkenyl or C₂ -C₁₅ -alkynyl,each of which is optionally substituted by fluorine, chlorine, bromine,C₁ -C₆ -alkoxy, C₁ -C₆ -alkylthio, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alkylamino, acetylamino, benzoylamino or by phenyl, it being possiblefor the phenyl radical in turn to carry one to three substituents fromthe group comprising nitro, trifluoromethyl, fluorine, chlorine,bromine, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy or C₁ -C₆ -alkylthio, or issubstituted by the group COR⁶,

R⁶ representing hydrogen, representing hydroxyl, representing C₁ -C₆-alkoxy or representing the group ##STR4## R⁷ and R⁸ being identical ordifferent and representing hydrogen, representing C₁ -C₆ -alkyl,representing phenyl, representing benzyl, representing acetyl orrepresenting benzoyl, or R⁷ and R⁸ together with the nitrogen atomforming a heterocycle from the series comprising pyrrolidine,piperidine, morpholine, thiomorpholine, imidazolidine, piperazine orpyrroline. or

R⁴ represents the group of the formula COR⁶,

R⁶ having the abovementioned meaning,

in the form of their isomers, isomer mixtures, racemates or opticalantipodes, and their physiologically acceptable salts.

Particularly preferred compounds of the formula I are those

in which

R¹ represents methyl or ethyl, each of which is optionally substitutedby chlorine, bromine or acetyloxy,

R² represents cyano, represents nitro or represents the group CO₂ R⁵,

R⁵ denoting straight-chain or branched C₁ -C₄ -alkyl which is optionallysubstituted by one or more fluorine, cyano, C₁ -C₄ -alkoxy, C₁ -C₄-alkylthio or N-benzylmethylamino,

R³ represents phenyl which is optionally substituted up to three times,identically or differently, by fluorine, chlorine, nitro, cyano, C₁ -C₄-alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, benzyl, benzyloxy orbenzylthio, it being possible for the phenyl radicals in turn to besubstituted up to twice by nitro, trifluoromethyl, methoxy, fluorine,chlorine, methyl or ethyl, or is substituted by trifluoromethyl ortrifluoromethoxy, or represents pyridyl, thienyl, furyl, pyrimidyl orbenzoxadiazolyl or 2-phenyl-thiochromen-8-yl, and

R⁴ represents phenyl which is optionally substituted up to twice,identically or differently, by fluorine, chlorine, nitro, C₁ -C₄ alkyl,C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio or trifluoromethoxy, or representsstraight-chain, branched or cyclic C₁ -C₁₀ -alkyl, C₂ -C₁₀ -alkenyl orC₂ -C₁₀ -alkynyl, each of which is optionally substituted by fluorine,chlorine, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio, amino, C₁ -C₄ -alkylamino,di-C₁ -C₄ -alkylamino, acetylamino or by phenyl, it being possible forphenyl in turn to carry one to two substituents from the groupcomprising nitro, trifluoromethyl, fluorine, chlorine, C₁ -C₄ -alkoxy orC₁ -C₄ -alkyl, or is substituted by the group COR⁶,

R⁶ representing hydrogen, representing hydroxyl, representing C₁ -C₄-alkoxy or representing the group ##STR5## R⁷ and R⁸ being identical ordifferent and representing hydrogen, representing C₁ -C₄ -alkyl,representing phenyl, representing benzyl or representing acetyl, or

R⁷ and R⁸, together with the nitrogen atom, form a heterocycle from theseries comprising pyrrolidine, piperidine, morpholine or thiomorpholine,or

R⁴ represents the group COR⁶,

R⁶ having the abovementioned meaning,

in the form of their isomers, isomer mixtures, racemates or opticalantipodes, and their physiologically acceptable salts.

Physiologically acceptable salts of the substances according to theinvention can be salts with inorganic or organic acids. Examples whichmay be mentioned are: hydrohalides, such as hydrobromides,hydrochlorides, hydrogen sulphates, sulphates, hydrogen phosphates,acetates, maleates, fumarates, citrates, tartrates, lactates orbenzoates.

The compounds according to the invention, of the general formula I inwhich R¹ -R⁴ have the abovementioned meaning, are obtained when

[A] aldehydes of the general formula (II) ##STR6## in which R³ has theabovementioned meaning, and keto compounds of the general formula (III)##STR7## in which R² and R³ have the abovementioned meaning, are reactedwith keto compounds of the general formula (IV) ##STR8## in which R⁴ hasthe abovementioned meaning, and ammonia, where appropriate in thepresence of water or inert organic solvents, or when

[B] aldehydes of the general formula (II) are reacted with ketocompounds of the general formula (III) and enamines of the generalformula (V) ##STR9## in which R⁴ has the abovementioned meaning, whereappropriate in the presence of water or inert organic solvents, or when

[C] aldehydes of the general formula (II) are reacted with ketocompounds of the general formula (IV) and enamines of the generalformula (VI) ##STR10## in which R¹ and R² have the abovementionedmeaning, where appropriate in the presence of water or inert organicsolvents, or when

[D] keto compounds of the general formula (III) and ammonia are reactedwith ylidene compounds of the general formula (VII) ##STR11## in whichR³ and R⁴ have the abovementioned meaning, where appropriate in thepresence of water or inert organic solvents, or when

[E] keto compounds of the general formula (IV) and ammonia are reactedwith ylidene compounds of the general formula (VIII) ##STR12## in whichR¹ -R₃ have the abovementioned meaning, where appropriate in thepresence of water or inert organic solvents, or when

[F] enamines of the general formula (VI) are reacted with ylidenecompounds of the general formula (VII), where appropriate in thepresence of water or inert organic solvents, or when

[G] enamines of the general formula (V) are reacted with ylidenecompounds of the general formula (VIII), where appropriate in thepresence of water or inert organic solvents, or when

[H] 1,4-dihydropyridinecarboxylic acids of the general formula (IX)##STR13## in which R¹ -R³ have the abovementioned meaning, are reactedby known methods, where appropriate via a reactive acid derivative, withcompounds of the general formula (X) ##STR14## in which R⁴ has theabovementioned meaning, where appropriate in the presence of an inertorganic solvent.

Examples of reactive acid derivatives which may be mentioned are:activated esters, hydroxysuccinimide esters, acid imidazolides, acidhalides, mixed anhydrides, reaction with cyclohexylcarbodiimide.

Depending on the nature of the starting materials used, the synthesis ofthe compounds according to the invention by processes A-H can beillustrated by the following equations: ##STR15##

The aldehydes of the formula (II) used as starting materials are knownor can be prepared by known methods [compare E. Mosettig, OrganicReactions Vol. III, 218 et seq. (1954); CA 59, 13929 (1963)].

The keto compounds of the formula (III) used as starting materials areknown or can be prepared by known methods [compare D. Borrmann,Houben-Weyls "Methoden der organischen Chemie" ("Methods of Organicchemistry") VII/4, 230 et seq. (1968); Y. Oikawa, K. Sugano, O.Yonemitsu, J. Org. Chem. 43, 2087 (1978); N. Levy, C. W. Scaife, J.Chem. Soc. (London) 1946, 1100; C. D. Hurd, M. E. Nilson, J. Org. Chem.20, 927 (1955), S. Gelin, P. Pollet, Synth. Commun. 1980, 805,Tetrahedron 34 1453 (1978)].

The enamines (VI) used as starting materials are known or can beprepared by methods known from the Literature [compare S. A. Glickmann,A. C. Cope, J. Chem. Soc. 67, 1017 (1945), H. Bohme, K.-H. Weisel, Arch.Pharm. 310, 30 (1977)].

The ylidene compounds (VIII) used as starting materials are known or canbe prepared by methods known from the literature [compare G. Jones "TheKnoevenagel Condensation", Organic Reactions XV, 204 et seq. (1967); forR⁵ =NO₂ compare w. Sassenberg A. Dornow, Liebigs Ann. Chem. 602, 14(1957)].

The 1,4-dihydropyridinecarboxylic acids (IX) used as starting materialsare known or can be prepared by known methods (compare German Pat. No.28 47 237, German Pat. No. 31 30 041, German Pat. No. 33 19 956, BelgianPatent 89 39 984, German Pat. No. 33 31 808).

The piperazines (X) used as starting materials are also known.

The compounds (IV), (V) and (VII) are new. They can be prepared bymethods known from the literature as described in the examples. Alsoaccording to, for example: D. Borrmann in Houben-Weyl, "Methoden derorganischen Chemie" ("Methods of Organic Chemistry"), Vol. VII/4, 230 etseq. (1968); G. Jones in Organic Reactions Vol. VI. 204 et seq. (1967);S. A. Glickmann, A. C. Cope in J. Amer. Chem. Soc. 67, 1017 (1945).

Suitable diluents for processes A-G are water or all inert organicsolvents. These preferably include alcohols such as methanol, ethanoland n- or iso-propanol, ethers such as diethyl ether, tetrahydrofuran,dioxane or glycol monomethyl or dimethyl ether, glacial acetic acid,pyridine, dimethylformamide, dimethyl sulphoxide, acetonitrile,hexamethyl phosphoric triamide or ethyl acetate. It is equally possibleto use mixtures of the solvents mentioned.

The customary inert organic solvents are suitable for process H. Thesepreferably include chlorinated hydrocarbons such as dichloromethane,trichloromethane, tetrachloromethane or 1,2-dichloroethane, or etherssuch as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane,or aromatic hydrocarbons such as benzene, toluene, or xylene, oracetonitrile, nitromethane, dimethylformamide, hexamethylphosphorictriamide, pyridine or ethyl acetate.

The reaction temperatures for all the processes can be varied within arelatively wide range. In general, processes A to G are carried out in arange from 10° C. to 200° C., preferably from 20° C. to 150° C. ProcessH is generally carried out in a range from -70° C. to +60° C.,preferably from -50° C. to +40° C.

The reaction can be carried out under atmospheric pressure as well asunder elevated pressure. In general, it is carried out under atmosphericpressure.

When carrying out the processes according to the invention, the ratio ofthe substances involved in the reaction is optional. However, ingeneral, molar amounts of the reactants are used. In process H it hasproved advantageous to use the amine in up to a 5-fold molar excess.

The compounds according to the invention exist in stereoisomeric formswhich either are related as image and mirror image (enantiomers) or arenot related as image and mirror image (diastereomers). The inventionrelates to both the antipodes and the racemic forms as well as mixturesof diastereomers. The racemic forms can be resolved in exactly the sameway as the diastereomers into the stereoisomerically homogeneousconstituents in a known manner (compare E. L. Eliel, Stereochemistry ofCarbon Compounds, McGraw Hill, 1962).

The substances influence the calcium balance in eukariotic cells. Thusthey are suitable as coronary therapeutic agents and can havecardioprotective or myocardium-stimulating actions. Furthermore, theycan have favorable effects on the blood pressure and normalize bloodsugar. They can have an effect on blood platelet aggregation.

The coronary and heart effects were found in the heart, undergoingisolated perfusion, of albino guineapigs of both sexes weighing 200 g,which was perfused with suitable dilutions of the sustances. For thispurpose, the animals were killed, the thorax was opened, a metal cannulawas tied into the aorta which had been exposed, and the left atrium wasopened.

The heart was dissected out with the lungs from the thorax and connectedvia the aorta cannula to the perfusion apparatus with perfusion inprogress. The lungs were severed at the roots of the lungs. Theperfusion medium used was a Krebs-Henseleit solution (118 mmol/l NaCl,4.8 mmol/l KCl, 1.2 mmol/l MgSO₄, 119 mmol/l MgSO₄, 25 mmol/l NaHCO₃,0.013 mmol/l NaEDTA, pH 7.4, 10 mmol/l glucose) containing 1.2 mmol ofCaCl₂, which had been filtered to remove particles before the perfusion.The hearts were perfused at 32° C. with a constant flow rate of 10ml/min. The contractions of the heart were measured isovolumetricallyusing a latex balloon introduced into the left ventricle and wererecorded on a high-speed pen recorder. The perfusion pressure wasrecorded as a measure of the coronary resistance.

The effects on contractility and coronary resistance of a few examplesof the compounds according to the invention are summarized in Table 1.

                  TABLE 1                                                         ______________________________________                                               Conc.    percentage change in                                          Ex. No.  (μg/ml) contract.                                                                              coron. resistance                                ______________________________________                                        22       1          -5       -6                                                        10         -52      -19                                              25       1          0        -10                                                       10         -9       -18                                              57       1          -49      -35                                                       10         -93      -38                                              54       1          -61      -66                                                       10         -77      -74                                              60       1          -30      -9                                                        10         -76      -12                                              17       1          +28      -40                                                       10         +48      -40                                              ______________________________________                                    

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, capsules, coated tablets,pills, granules, aerosols, syrups, emulsions, suspensions and solutions,using inert, non-toxic, pharmaceutically suitable vehicles or solvents.The therapeutically active compounds should in each case be present in aconcentration of about 0.5 to 90% by weight of the total mixture, thatis to say in amounts which suffice to achieve the dosage rangeindicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or vehicles, optionally with the use ofemulsifiers and/or dispersing agents, and, for example, when using wateras a diluent, organic solvents can optionally be used as auxiliarysolvents.

Examples of auxiliaries which may be mentioned are: water, non-toxicorganic solvents, such as paraffins (for example petroleum fractions),vegetable oils (for example groundnut oil/sesame oil), alcohols (forexample ethyl alcohol and glycerol) and glycols (for example propyleneglycol and polyethylene glycol), solid vehicles, such as, for example,natural rock powders (for example kaolins, aluminas, talc and chalk),synthetic rock powders (for example highly disperse silica andsilicates) and sugars (for example sucrose, lactose and glucose),emulsifiers (for example polyoxyethylene fatty acid esters),polyoxyethylene fatty alcohol ethers (for example lignin, sulphite wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium sulphate).

Administration is effected in the customary manner, preferably orally orparenterally, in particular perlingually or intravenously. In the caseof oral administration, the tablets can, of course, also contain, inaddition to the vehicles mentioned, additives such as sodium citrate,calcium carbonate and dicalcium phosphate, together with variousadditional substances, such as starch, preferably potato starch,gelatine and the like. Furthermore, lubricants such as magnesiumstearate, sodium lauryl sulphate and talc can also be used when makingtablets. In the case of aqueous suspensions and/or elixirs which areintended for oral use, the active compounds can be mixed with variousflavor-improving agents or colorants in addition to the abovementionedauxiliaries.

In the case of parenteral administration, solutions of the activecompounds, employing suitable liquid vehicles, can be used.

In general, it has proved advantageous, in the case of intravenousadministration, to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg, body weight to achieve effectiveresults, and in the case of oral administration, the dosage is about0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg, body weight.

Nevertheless, it can at times be necessary to deviate from the amountsmentioned, and in particular to do so as a function of the body weightof the experimental animal or of the nature of the administrationmethod, but also because of the species of animal and its individualbehavior towards the medicament, or the nature of the formulation of themedicament and the time or interval over which the administration takesplace. Thus it can suffice in some cases to manage with less than theabove-mentioned minimum amount, while in other cases the upper limitmentioned must be exceeded. Where relatively large amounts areadministered, it can be advisable to divide these into severalindividual administrations over the course of the day. The same dosagerange is envisaged for administration in human medicine. In thisconnection, the above statements similarly apply.

PREPARATION EXAMPLES Example 1 3-Aminocrotonic acid4-cyclohexylpiperazide ##STR16## (a) 3-Oxo-butyric acid4-cyclohexylpiperazide

24 g (0.1 mol) of 1-cyclohexylpiperazine are suspended in 150 ml ofabsolute tetrahydrofuran. 20 ml of triethylamine are poured in and,after 20 minutes, 18.6 g of diketene in 20 ml of tetrahydrofuran areadded dropwise, and the mixture is then stirred at room temperature for2 h. Thereafter part of the solvent is removed by distillation in vacuo,the mixture is poured onto 200 ml of ice-water, 20 g of Na₂ CO₃ areadded, and extraction is carried out 3 times with 50 ml of methylenechloride each time. After the organic phase has been dried with MgSO₄,crude 3-oxo-butyric acid 4-cyclohexylpiperazide is obtained as theresidue from evaporation.

(b) 3-Aminocrotonic acid 4-cyclohexylpiperazide

0.1 mol of crude 3-oxo-butyric acid 4-cyclohexylpiperazide is dissolvedin 150 ml of tetrahydrofuran and, under reflux, after addition of 0.5 gof p-toluenesulphonic acid, ammonia is passed in for 4 hours. Themixture is allowed to stand at room temperature overnight, the solventis removed by distillation in vacuo, and the residue is crystallizedfrom toluene/petroleum ether.

Yield: 18.6 g (74% of theory)

Melting point: 92° C.

The compounds listed in Table 2 were synthesized in analogy to Example1.

                  TABLE 2                                                         ______________________________________                                         ##STR17##                                                                                               Melting point                                      Ex. No.   R.sup.4          [°C.]                                       ______________________________________                                                   ##STR18##       141° C.                                     3         CH.sub.2CH(CH.sub.3).sub.2                                                                     Oel                                                4         CH.sub.2CHCH.sub.2                                                                             Oel                                                5         CH.sub.2CCH      Oel                                                6         CH(CH.sub.3).sub.2                                                                             208° C.                                     7                                                                                        ##STR19##       186° C.                                     8                                                                                        ##STR20##       150° C.                                     9                                                                                        ##STR21##        78° C.                                     10                                                                                       ##STR22##       Oel                                                11                                                                                       ##STR23##        75° C.                                     ______________________________________                                    

Example 121,4-Dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-carboxylicacid 4-cyclohexylpiperazide ##STR24##

17.4 g (0.10 mol) of 2-trifluoromethylphenylbenzaldehyde, 12.0 g (0.12mol) of nitroacetone and 25.1 g (0.10 mol) of β-aminocrotonic acid4-cyclohexylpiperazide are heated in 50 ml of isopropanol at 60° C. for12 hours. On cooling, the product separates out and is recrystallizedfrom isopropanol.

Yield: 23.6 g (48% of theory)

Melting point: 240° C. (decomposition)

Example 135-Carboxymethyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid 4-cyclopentylpiperazide ##STR25##

15.1 g (0.10 mol) of 3-nitrobenzaldehyde, 25.2 g (0.10 mol) ofacetoacetic acid 4-cyclopentylpiperazide and 12.9 g (0.10 mol) ofisopropyl β-aminocrotonate are heated to reflux in 60 ml of isopropanolfor 12 hours. The product crystallizes on trituration. Recrystallizationfrom isopropanol.

Yield: 29.4 g (61% of theory)

Melting point: 130° C.

Example 145-Carboxymethyl-4-(2-chlorophenyl)-dihydro-2,6-dimethylpyridine-3-carboxylicacid 4-isopropylpiperazide ##STR26##

11.9 g (50 mmol) of methyl 2-chlorobenzylideneacetoacetate and 10.5 g(50 mmol) of 3-aminocrotonic acid 4-isopropylpiperazide are heated toreflux in 50 ml of isopropanol for 12 hours. The product crystallizesafter cooling.

Yield: 1.7 g (79% of theory)

Melting point: 214° C.

Example 154-(2,1,3-Benzoxadiazol-4-yl)-1.4-dihydro-2.6-dimethyl-5-nitro-pyridine-3-carboxylicacid 4-(3-trifluoromethylphenyl) piperazide ##STR27##

7.4 g (50 mmol) of 2.1.3-benzoxadiazole-4-aldehyde, 10 g (0.1 mol) ofnitroacetone and 15.6 g (50 mmol) of 3-aminocrotonic acid4-(3-trifluoromethylphenyl)piperazide are heated in isopropanol at 60°C. for 6 hours. The product crystallizes after part of the solvent hasbeen evaporated off, and is recrystallized from a little isopropanol.

Yield: 8.9 g (34% of theory)

Melting point: 219° C.

Example 164-(2-Benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylicacid 4-(2-trifluoromethylphenylethyl)piperazide ##STR28##

2.97 g (10 mmol) of 1-(-2-benzyloxyphenyl)-2-nitro-1-buten-3-one and2.96 g (mmol) of 3-aminocrotonic acid4-(2-trifluoromethylphenylethyl)piperazide are heated in 15 ml ofisopropanol at 60° C. for 4 hours. After cooling, a crude product isobtained, and this is recrystallized from a littel ethanol.

Yield: 3.45 g (55% of theory)

Melting point: 198° C.

Example 171,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-nitrophenyl)pyridine-3-carboxylicacid 4-phenylpiperazide ##STR29## (a)2-Acetyl-3-(3-nitrophenyl)-2-propenoic acid 4-phenylpiperazide

24.6 g (0.1 mol) of 3-oxo-butyric acid 4-phenylpiperazide in 60 ml ofacetic anhydride are induced to react with 20.6 g (0.1 mol) of1-n-butyliminomethyl-3-nitrobenzene. The mixture is then poured ontoice-water and hydrolyzed. The oil which separates out is taken up inmethylene chloride, washed with dilute bicarbonate solution and water,and dried with magnesium sulphate. After the solvent has been removed byevaporation, a crude benzylidene compound is obtained and is used assuch.

(b)1,4-Dihydro-2,6-dimethyl-5-nitro-4-(3-nitrophenyl)pyridine-3-carboxylicacid 4-phenylpiperazide

2.5 g (10 mmol) of crude 2-acetyl-3-(3-nitrophenyl)-2-propenoic acid4-phenyl-piperazide and 2.5 g (25 mmol) of 2-amino-1-nitro-1-propene areheated in 15 ml of isopropanol at 60° C. for 6 hours. The crude productwhich has precipitated out is crystallized from isopropanol.

Yield: 2.7 g (58% of theory)

Melting point: 200° C.

Example 185-Carboxymethyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3-carboxylicacid 4-phenyl-piperazide ##STR30##

1.1 g (6.5 mmol) of carbonyldiimidazole are added to 1.60 g (5 mmol) of5-carboxymethyl-4-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylicacid suspended in 20 ml of absolute tetrahydrofuran. The mixture isstirred at room temperature for 30 minutes and at a reflux temperaturefor 30 minutes. 1.62 g (10 mmol) of phenylpiperazine in 5 ml of absolutetetrahydrofuran are added to the resulting solution. This mixture isheated to reflux for 3.5 hours and then evaporated, the residue is takenup in methylene chloride, and the solution is washed successively with1N hydrochloric acid, 1N sodium hydroxide solution and water, dried withmagnesium sulphate and again evaporated. The residue crystallizes fromisopropanol.

Yield: 1.82 (78% of theory)

Melting point: 182° C.

The 1.4-dihydropyridine-3-carboxylic acid piperazides which wereprepared in analogy to the foregoing Examples 12 to 18 are compiled inTables 3 and 4.

                                      TABLE 3                                     __________________________________________________________________________     ##STR31##                                                                    Example No.                                                                          R.sup.3            R.sup.4      Melting point (°C.)             __________________________________________________________________________    19                                                                                    ##STR32##                                                                                        ##STR33##   228 (decomp.)                          20                                                                                    ##STR34##                                                                                        ##STR35##   117 (decomp.)                          21                                                                                    ##STR36##                                                                                        ##STR37##   228 (decomp.)                          22                                                                                    ##STR38##                                                                                        ##STR39##   203 (decomp.)                          23                                                                                    ##STR40##                                                                                        ##STR41##   261 (decomp.)                          24                                                                                    ##STR42##                                                                                        ##STR43##   278 (decomp.)                          25                                                                                    ##STR44##         CH.sub.2CH(CH.sub.3).sub.2                                                                 248                                    26                                                                                    ##STR45##         CH.sub.2CH(CH.sub.3).sub.2                                                                 218                                    27                                                                                    ##STR46##         CH.sub.2CH(CH.sub.3).sub.2                                                                 225 (decomp.)                          28                                                                                    ##STR47##         CH.sub.2CHCH.sub.2                                                                         190                                    29                                                                                    ##STR48##         CH.sub.2CHCH.sub.2                                                                         223 (decomp.)                          30                                                                                    ##STR49##         CH.sub.2CHCH.sub.2                                                                         263 (decomp.)                          31                                                                                    ##STR50##         CH.sub.2CCH  233 (decomp.)                          32                                                                                    ##STR51##         CH.sub.2CCH  176                                    33                                                                                    ##STR52##         CH.sub.2 CCH 214                                    34                                                                                    ##STR53##         CH.sub.2 (CH.sub.3).sub.2                                                                  262 (decomp.)                          35                                                                                    ##STR54##         CH(CH.sub.3).sub.2                                                                         250 (decomp.)                          36                                                                                    ##STR55##         CH(CH.sub.3).sub.2                                                                         200 (decomp.)                          37                                                                                    ##STR56##         CH(CH.sub.3).sub.2                                                                         227                                    38                                                                                    ##STR57##         CH(CH.sub.3).sub.2                                                                         271 (decomp.)                          39                                                                                    ##STR58##         CH(CH.sub.3).sub.2                                                                         resin                                  40                                                                                    ##STR59##                                                                                        ##STR60##   274 (decomp.)                          41                                                                                    ##STR61##                                                                                        ##STR62##   187                                    42                                                                                    ##STR63##                                                                                        ##STR64##   212                                    43                                                                                    ##STR65##                                                                                        ##STR66##   273                                    44                                                                                    ##STR67##                                                                                        ##STR68##   249                                    45                                                                                    ##STR69##                                                                                        ##STR70##   265 (decomp.)                          46                                                                                    ##STR71##                                                                                        ##STR72##   121                                    47                                                                                    ##STR73##                                                                                        ##STR74##   183                                    48                                                                                    ##STR75##                                                                                        ##STR76##   195 (decomp.)                          49                                                                                    ##STR77##                                                                                        ##STR78##   118                                    50                                                                                    ##STR79##                                                                                        ##STR80##   266 (decomp.)                          51                                                                                    ##STR81##                                                                                        ##STR82##   165                                    52                                                                                    ##STR83##                                                                                        ##STR84##   173                                    53                                                                                    ##STR85##                                                                                        ##STR86##   163                                    __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR87##                                                                    Example                          Melting                                      No.  R.sup.3         R.sup.4  R.sup.5                                                                          point (°C.)                           __________________________________________________________________________    54                                                                                  ##STR88##                                                                                     ##STR89##                                                                             CH.sub.3                                                                         186                                          55                                                                                  ##STR90##                                                                                     ##STR91##                                                                             CH.sub.3                                                                         266                                          56                                                                                  ##STR92##      CH.sub.2CCH                                                                            C.sub.2 H.sub.5                                                                  170                                          57                                                                                  ##STR93##      CH.sub.2CCH                                                                            CH.sub.3                                                                         202                                          58                                                                                  ##STR94##      CH(CH.sub.3).sub.2                                                                     CH.sub.3                                                                         239                                          59                                                                                  ##STR95##      CH(CH.sub.3).sub.2                                                                     C.sub.2 H.sub.5                                                                  146                                          60                                                                                  ##STR96##      CH(CH.sub.3).sub.2                                                                     C.sub.2 H.sub.5                                                                  209 (decomp.)                                61                                                                                  ##STR97##      CH(CH.sub.3).sub.2                                                                     C.sub.2 H.sub.5                                                                  resin                                        62                                                                                  ##STR98##                                                                                     ##STR99##                                                                             C.sub.2 H.sub.5                                                                  194                                          63                                                                                  ##STR100##                                                                                    ##STR101##                                                                            C.sub.2 H.sub.5                                                                  resin                                        64                                                                                  ##STR102##                                                                                    ##STR103##                                                                            C.sub.2 H.sub.5                                                                  156                                          65                                                                                  ##STR104##                                                                                    ##STR105##                                                                            C.sub.2 H.sub.5                                                                  145                                          66                                                                                  ##STR106##                                                                                    ##STR107##                                                                            CH.sub.3                                                                         182                                          67                                                                                  ##STR108##                                                                                    ##STR109##                                                                            CH.sub.3                                                                         240 (decomp.)                                68                                                                                  ##STR110##                                                                                    ##STR111##                                                                            CH.sub.3                                                                         resin                                        __________________________________________________________________________

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

We claim:
 1. A 1,4-dihydropyridine-3-carboxylic acid piperazide offormula ##STR112## in which R¹ represents cyano or representsstraight-chain or branched C₁ -C₆ -alkyl which is optionally substitutedby halogen, hydroxyl, benzoyloxy or acetyloxy,R³ represents C₆ -C₁₂-aryl which is optionally substituted once or several times, identicallyor differently, by halogen, nitro, cyano, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy,C₁ -C₈ -alkylthio, C₇ -C₁₄ -aralkyl, C₇ -C₁₄ -aralkoxy or C₇ -C₁₄-aralkylthio, it being possible for each of the aryl radicals in turn tobe substituted by nitro, trifluroro-methyl, cyano, methoxy, methylthio,trifluoro-methoxy, difluoromethoxy, halogen, or C₁ -C₆ -alkyl, or isoptionally substituted by trifluoromethyl, trifluoromethylthio,trifluoromethoxy, difluoromethoxy, amino, C₁ -C₆ -alkyl-amino, di-C₁-C-alkylamino, acetylamino or by benzylmethylamino, or represents aheterocycle from the group consisting of pyridyl, thienyl, furyl,pyrrolyl, quinolyl, isoquinolyl, pyrimidyl, benzoxadiazolyl, imidazolyl,thiazolyl, oxazolyl, chromenyl, or thiochromenyl, the heterocycleoptionally being substituted by phenyl, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy,C₁ -C₆ -alkylthio, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, halogen, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alklamino, acetylamino or benzylmethylamino, and R⁴ represents C₆ -C₁₂-aryl which is optionally substituted once or several times, identicallyor differently, by halogen, nitro, cyano, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy,C₁ -C₈ -alkylthio, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, difluoromethoxy, hydroxyl, amino, C₁ -C₆ -amino,di-C₁ -C₆ alkylamino, acetylamino or benzylmethylamino, or representsstraight-chain, branched or cyclic C₁ -C₂₀ -alkyl, C₂ -C₂₀ alkenyl or C₂-C₂₀ -alkynyl, each of which can optionally be substituted by halogen,C₁ -C₈ -alkoxy, C₁ -C₈ -alkyl-thio, amino, C₁ -C₈ -alkylamino, di-C₁ -C₈-alkyl-amino, acetylamino, benzylmethylamino, piperidino, piperazino,morpholino, thiomorpholino, pyrrolidino or by C₆ -C₁₂ -aryl, it beingpossible for aryl in turn to carry one or more substituents from thegroup consisting of nitro, cyano, trifluoromethyl, halogen, C₁ -C₈-alkyl, C₁ -C₈ -alkylthio or C₁ -C₈ -alkoxy, or is substituted by thegroup COR⁶, R⁶ representing hydrogen, representing hydroxy, representingC₁ -C₈ -alkoxy or representing the group ##STR113## R⁷ and R⁸ beingidentical or different and denoting hydrogen, C₁ -C₈ -alkyl, C₆ -C₁₂-aryl, C₆ -C₁₄ -aralkyl, acetyl or benzoyl, or R⁷ and R⁸ togetherforming a 5-7 membered saturated or unsaturated ring which can containsas further hetero atoms nitrogen, sulphur and/or oxygen, or R⁴represents the group COR⁶, or a physiologically acceptable salt thereof.2. A dihydropyridine or salt according to claim 1, in whichR¹ representsstraight-chain or branched C₁ -C₄ -alkyl, which is optionallysubstituted by one or more fluorine, chlorine, bromine, hydroxyl,benzoyloxy or acetyloxy, R³ represents phenyl which is optionallysubstituted up to four times, identically or differently, by fluorine,chlorine, bromine, nitro, cyano, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, C₁ -C₆-alkylthio, benzyl, benzyloxy or benzylthio, it being possible for eachof the phenyl radicals in turn to be substituted by nitro,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxy,fluorine, chlorine, bromine or C₁ -C₄ -alkyl, or is substituted bytrifluoromethyl, trifluoromethoxy, difluoromethoxy, amino, C₁ -C₄-alkylamino, di-C₁ -C₄ -alkylamino or acetylamino, or representspyridyl, thienyl, furyl, pyrimidyl, benzoxadiazolyl,2-phenyl-thiochromen-8-yl or quinolyl, and R⁴ represents phenyl which isoptionally substituted up to four times, identically or differently, byfluorine, chlorine, bromine, nitro, cyano, C₁ -C₆ -alkyl, C₁ -C₆-alkoxy, C₁ -C₆ -alkylthio, trifluoromethyl, trifluoromethoxy,difluoromethoxy, hydroxyl, amino, C₁ -C₃ -alkylamino, di-C₁ -C₃-alkylamino or acetylamino, or represents straight-chain, branched orcyclic C₁ -C₁₅ -alkyl, C₂ -C₁₅ -alkenyl or C₂ -C₁₅ -alkynyl, each ofwhich is optionally substituted by fluorine, chlorine, bromine, C₁ -C₆-alkoxy, C₁ -C₆ -alkylthio, amino, C₁ -C₆ -alkylamino, di-C₁ -C₆-alkylamino, acetylamino, benzoylamino or by phenyl, it being possiblefor the phenyl radical in turn to carry one to three substituents fromthe group consisting of nitro, trifluoromethyl, fluorine, chlorine,bromine, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy or C₁ -C₆ -alkylthio, or issubstituted by the group COR⁶, R⁶ represents hydrogen, representinghydroxyl, representing C₁ -C₆ -alkoxy or representing the group##STR114## R⁷ and R⁸ being indentical or different and representinghydrogen, representing C₁ -C₆ -alkyl, representing phenyl, representingbenzyl, representing acetyl or representing benzoyl, or R⁷ and R⁸together with the nitrogen atom forming a heterocycle from the groupconsisting of pyrrolidine, piperidine, morpholine, thiomorpholine,imidazolidine, piperazine or pyrroline, or R⁴ represents the group ofthe formula COR⁶.
 3. A dihydropyridine or salt according to claim 1, inwhichR¹ represents methyl or ethyl, each of which is optionallysubstituted by chlorine, bromine or acetyloxy, R³ represents phenylwhich is optionally substituted up to three times, identically ordifferently, by fluorine, chlorine, nitro, cyano, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, benzyl, benzyloxy or benzylthio, it beingpossible for the phenyl radicals in turn to be substituted up to twiceby nitro, trifluoromethyl, methoxy, fluorine, chlorine, methyl or ethyl,or is substituted by trifluoromethyl or trifluoromethoxy, or representspyridyl, thienyl, furyl, pyrimidyl or benzoxadiazolyl or2-phenyl-thiochromen-9-yl, and R⁴ represents phenyl which is optionallysubstituted up to twice, identically or differently, by fluorine,chlorine, nitro, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, C₁ -C₄ -alkylthio ortrifluoromethoxy, or represents straight-chain, branched or cyclic C₁-C₁₀ -alkyl, C₂ -C₁₀ -alkenyl or C₂ -C₁₀ -alkynyl, each of which isoptionally substituted by fluorine, chlorine, C₁ -C₄ -alkoxy, C₁ -C₄-alkylthio, amino, C₁ -C₄ -alkylamino, di-C₁ -C₄ -alkylamino,acetylamino or by phenyl, it being possible for phenyl in turn to carryone to two substituents from the group consisting of nitro,trifluoromethyl, fluorine, chlorine, C₁ -C₄ -alkoxy or C₁ -C₄ -alkyl, oris substituted by the group COR⁶, R⁶ represents hydrogen, representinghydroxyl, representing C₁ -C₄ -alkoxy or representing the group##STR115## R⁷ and R⁸ being identical or different and representinghydrogen, representing C₁ -C₄ alkyl, representing phenyl, representingbenzyl or representing acetyl, or R⁷ and R⁸, together with the nitrogenatom, form a heterocycle from the group consisting of pyrrolidine,piperidine, morpholine or thiomorpholine, or R⁴ represents the groupCOR⁶.
 4. A dihydropyridine according to claim 1, wherein such compoundis1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-3-carboxylicacid 4-cyclohexylpiperazide of the formula ##STR116## or aphysiologically acceptable salt thereof.
 5. A dihydropyridine accordingto claim 1, wherein such compound is4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylicacid 4-(3-trifluoromethyl-phenyl) piperazide of the formula ##STR117##or a physiologically acceptable salt thereof.
 6. A dihydropyridineaccording to claim 1, wherein such compound is4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylicacid 4-(2-trifluoromethylphenyl-ethyl)piperazide of the formula##STR118## or a physiologically acceptable salt thereof.
 7. Acardioprotective and myocardium-stimulating composition comprising anamount effective therefor of a compound or salt according to claim 1 inadmixture with a diluent.
 8. A unit dose of a composition according toclaim 7 in the form of a tablet, capsule or ampule.
 9. A method ofnormalizing circulation in a patient in need thereof which comprisesadministering to such patient an amount effective therefor of a compoundor salt according to claim
 1. 10. The method according to claim 9,wherein such compoundis1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethyl-phenyl)-pyridine-3-carboxylicacid 4-cyclohexylpiperazide,4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxylicacid 4-(3-trifluoromethyl-phenyl)piperazide, or4-(2-benzyloxyphenyl-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylicacid 4-(2-trifluoro-methylphenylethyl)piperazide,or a physiologicallyacceptable salt thereof.